The first synthesis of an epidiselenodiketopiperazine

Article abstract of DOI:10.1021/ol3020094

Epidithiodiketopiperazines (ETPs) are natural products (e.g., gliotoxin) with varied and important biological activity, which often is attributed to the redox properties of the disulfide moiety. As such, analogs with altered redox properties and similar s

Full text of DOI:10.1021/ol3020094

ORGANIC
LETTERS
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Vol. XX, No. XX
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The First Synthesis of an
Epidiselenodiketopiperazine
Travis C. McMahon,† Sarah Stanley,‡ Edward Kazyanskaya,‡ Deborah Hung,‡ and
John L. Wood*,†
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States, and The Broad Institute, Infectious Disease Initiative, 7 Cambridge
Center, Cambridge, Massachusetts 02142, United States
john.l.wood@colostate.edu
Received July 19, 2012
ABSTRACT
Epidithiodiketopiperazines (ETPs) are natural products (e.g., gliotoxin) with varied and important biological activity, which often is attributed to
the redox properties of the disulfide moiety. As such, analogs with altered redox properties and similar structural characteristics would be of value
to biological investigations. The use of an ETP as the point of departure in the first synthesis of an epidiselenodiketopiperazine (ESeP) and its
activity against Mycobacterium tuberculosis (MTB) is reported.
Approximately one-third of the global population is
infected with tuberculosis, caused by Mycobacterium
tuberculosis (MTB), leading to nearly two million deaths
annually.1 Although there are known cures for MTB, most
of the problems associated with TB reside in developing
countries that lack the infrastructure and resources to
efficiently diagnose and then begin and complete treat-
ment. This establishes a clear and continuing need for
economically accessible treatments, and the growing pre-
Figure 1. Gliotoxin (1) and dehydrogliotoxin (2).
sence of TB strains resistant to current drug regimes serves
to accentuate this need. In 1950 Gliotoxin (1)2 was shown
to inhibit MTB with minimum inhibitory concentrations
exploration as anti-TB agents.5 Importantly, the gliotoxin
family represents only a subset of a growing number of
epidithiodiketopiperzine (ETP) natural products that have
been isolated and shown to possess a broad range of
interesting biological acitivities wherein the mode of action
has yet to be fully delineated;6 however, it is believed that
the bridging disulfide plays a major role. Unfortunately,
the redox processes in which the disulfide moiety engages is
also the likely culprit when it comes to the general toxicity
(MICs) ranging from 6 to 45 nM.3 As part of a collabora-
tive effort we recently reported a formal total synthesis of
dehydrogliotoxin4 (2) and demonstrated that this natural
product is active against MTB with an MIC of 130 nM,
thus establishing the broader gliotoxin family of natural
products (Figure 1) as potential candidates for further
† Colorado State University.
‡ The Broad Institute.
(1) Wright, A.; Zignol, M. Anti-Tuberculosis Drug Resistance in the
World; World Health Organization; Geneva, 2008; Vol. Report No. 4.
(2) (a) Weindling, R.; Emerson, O. H. Phytopathology 1936, 26, 1068.
(b) Bell, M. R.; Johnson, J. R.; Wildi, B. S.; Woodward, R. B. J. Am.
Chem. Soc. 1958, 80, 1001.
(3) Tompsett, R.; McDermott, W.; Kidd, J. G. J. Immunol. 1950, 65, 59.
(4) Lowe, G.; Taylor, A.; Vining, L. C. J. Chem. Soc. C 1966, 1799.
(5) McMahon, T. C.; Stanley, S.; Kazyanskaya, E.; Hung, D.; Wood,
J. L. Tetrahedron Lett. 2011, 52, 2262.
(6) (a) Jiang, C.-S.; Guo, Y.-W. Mini-Rev. Med. Chem. 2011, 11, 728.
(b) Gardiner, D. M.; Waring, P.; Howlett, B. J. Microbiology 2005, 151,
1021.
r
10.1021/ol3020094
XXXX American Chemical Society

of ETPs.7 Given that the intracellular redox potential has
been shown to vary at different stages of the cell cycle and
in different diseases, we recognized that accessing and
studying ETP-analogs with altered redox properties could
provide insight into the possibity of developing com-
pounds that would, on this basis, selectively engage dis-
eased cells.8 In our initial studies to this end we were
interested in replacing the disulfide with a diselenide.9
Herein we report the initial stages of this study which have
culminated in the first synthesis of an epidiselenodiketopi-
perazine (ESeP).
diselenide 4 was formed, presumably through the corre-
sponding acyl-iminium intermediate (Scheme 1).
Scheme 1. Synthesis of Diselenide 4 from DKP 3
Due to their structural complexity the ETP family of
natural products have received considerable attention
from the synthetic community,10 and several syntheses
have appeared recently.11 Although compounds in this
class have clearly become more accessible there remains an
absence of reports describing analogs wherein either one or
both sulfur atoms have been replaced by selenium.12 In
fact, a literature search revealed only a limited number of
bicyclic bridging diselenides,13 none of which were incor-
porated into a [2.2.2] framework. Unbiasedby any reported
appraoches to ESePs we decide to develop a method that
would allow for the conversion of an ETP to the corre-
sponding ESeP, a strategy that would potentially enable
one to employ gliotoxin, dehydrogliotoxin, or any other
epidithiodiketopiperazine as a point of departure.
Having established the viability of preparing a bridging
diselenide from an intermediate bis-electrophile, we fo-
cused our efforts on the ETP to ESeP conversion. To this
end it was envisioned that reduction of the disulfide and
capture of the intermediate thiolates as their thiomethyl
ethers would set the stage for an activation step wherein an
intermediate bissulfonium (7) would give rise to the requi-
site acyl-iminium ion. Capture of this intermediate with
a diselenide dianion equivalent in a manner analogous
to our model study would then furnish the desired ESeP
(4, Scheme 2).
Prior to investigating an ETP to ESeP conversion we
chose to familiarize ourselves with the potential reagents
by exploring the conversion of a simple diketopiperzine
(DKP) to the corresponding ESeP. To this end, known
DKP 3 was converted to its correpsonding dibromide14
whichwasthensubjected toa diselenide dianion equivalent
under conditions developed by Krief and Derock.15
Gratifyingly, under these conditions the desired bridging
Scheme 2. Planned Synthesis of Diselenide 4 from Disulfide 5
(7) Bernardo, P. H.; Brasch, N.; Chai, C. L. L.; Waring, P. J. Biol.
Chem. 2003, 278, 46549.
(8) Sarsour, E. H.; Kumar, M. G.; Chaudhuri, L.; Kalen, A. L.;
Goswami, P. C. Antioxid. Redox Signal. 2009, 11, 2985.
(9) The redox potentials (E0) of model peptides containing diselenide
(E0 = À381 mV) and selenosulfide (E0 = À326 mV) bonds have been
determined using dithiothreitol (E0 = À323 mV, pH 7.0) as a reference;
see: Besse, D.; Siedler, F.; Diercks, T.; Kessler, H.; Moroder, L. Agnew.
Chem., Int. Ed. Engl. 1997, 36, 883.
(10) For seminal reports, see: (a) Fukuyama, T.; Nakatsuka, S.-I.;
Kishi, Y. Tetrahedron 1981, 37, 2045. (b) Fukuyama, T.; Kishi, Y. J. Am.
Chem. Soc. 1976, 98, 6723. (c) Kishi, Y.; Fukuyama, T.; Nakatsuka, S.
J. Am. Chem. Soc. 1973, 95, 6492.
(11) For recent syntheses of ETP natural products, see: (a) DeLorbe,
J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am.
Chem. Soc. 2011, 133, 6549. (b) Codelli, J. A.; Puchlopek, A. L. A.;
Reisman, S. E. J. Am. Chem. Soc. 2011, 134, 1930. (c) Kim, J.;
Movassaghi, M. J. Am. Chem. Soc. 2010, 132, 14376. (d) Iwasa, E.;
Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078. (e) Kim, J.; Ashenhurst,
J. A.; Movassaghi, M. Science 2009, 324, 238.
To convert disulfide 5 to bisthiomethyl ether 6 we
first opened the disulfide with NaBH4 and then treated
the resultant dithiol with iodomethane.16 To activate the
bisthiomethyl ether we envisioned treating it with a variety
of electrophiles including methylating reagents (to form
dimethyl sulfide as a leaving group) or halogenating re-
agents. Ultimately bromine proved best, giving dibromide
9 when added to bisthiomethyl ether 6. As previously es-
tablished the dibromide could be treated with the disele-
nide dianion equivalent to afford diselenide 4 (Scheme 3).
Having gained access for the first time toan ESeP (i.e., 4)
we decided to briefly look at its biological activity against
MTB. For comparative purposes we also explored the
activity of disulfide 5 and the corresponding bismethylthio-
and bismethylseleno-analogs of 4 and 5 (i.e., 6 and 10,
(12) To the best of our knowledge, replacement of sulfur with
selenium has not been reported; however, the dioxo- and dinitrogen
analogs have. See: (a) Markham, J. L.; Sammes, P. G. J. Chem. Soc.,
Perkin Trans. 1 1979, 1885. (b) Sanz-Cervera, J. F.; Williams, R. M.;
ꢀ
ꢀ
ꢀ
Marco, J. A.; Lopez-Sanchez, J. M.; Gonzalez, F.; Martınez, M. E.;
´
ꢀ
Sancenon, F. Tetrahedron 2000, 56, 6345.
(13) (a) Tonkikh, N.; Duddeck, H.; Petrova, M.; Neilands, O.;
Strakovs, A. Eur. J. Org. Chem. 1999, 1999, 1585. (b) Sureshkumar,
D.; Ganesh, V.; Chandrasekaran, S. J. Org. Chem. 2007, 72, 5313.
(14) Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.; Dung,
J. S.; Anderson, O. P. J. Am. Chem. Soc. 1985, 107, 3246.
ꢀ
(16) Cook, K. M.; Hilton, S. T.; Mecinovic, J.; Motherwell, W. B.;
(15) Krief, A.; Derock, M. Synlett 2005, 2005, 1012.
Figg, W. D.; Schofield, C. J. J. Biol. Chem. 2009, 284, 26831.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Diselenide 4 from Disulfide 5
Scheme 4. Synthesis of Bisselenomethyl Ether 10
not as potent, did show activity against MTB with an IC50
of 16.2 μM.19
In summary, we have prepared the first epidiselenodi-
ketopiperazine (ESeP) and established the viability of a
route which employs ETPs as the point of departure. In
addition, we have demonstrated that the derived ESeP
shows activity against MTB that is comparable to the
correpsonding ETP. Investigations into the application
of this method in more complex systems such as gliotoxin
and dehydrogliotoxin as well as studies into the differential
effects of ETPs and ESePs are ongoing and willbe reported
in due course.
respectively). Our interest in the latter compounds was
based on a study by Trown which demonstrated that
conversion of the ETP acetylaranotin to its bisthiomethyl
ether results in the loss of antiviral activity.17 In the event,
the bisselenomethyl ether 10 was prepared in a similar
fashion to 6 (Scheme 4), and the four compounds were
assayed for their activity against MTB. Disulfide 5 which
mimics the epidithiodiketopiperazine natural products
exhibited an IC50 of 2.3 μM. Gratifyingly, diselenide 4
showed comparable activity to that of the disulfide, with
an IC50 of 2.7 μM. Similar to what Trown observed, no
activity was observed when the disulfide was replaced with
a bisthiomethyl ether or when a methylene linker18 was
added. Interestingly bisselenomethyl ether 10, although
Acknowledgment. Dr. Chris Rithner, Don Heyse, and
Don Dick of the CSU Central Instrumentation Facility are ac-
knowledged for their assistance with spectroscopic analyses.
Research support from Amgen is gratefully acknowledged.
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR for all new com-
(17) Trown, P. W. Biochem. Biophys. Res. Commun. 1968, 33, 402.
(18) For the synthesis of the compound where a methylene linker is
placed in the bridging disulfide, see the Supporting Information.
(19) For experimental details of the assay run, see the Supporting
Information.
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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